Powerful Cholesterol-Lowering Drugs on Their Way

There are plenty of Food and Drug Administration approved cholesterol-lowering drugs available for patients. And they're quite powerful. Statins, such as Pfizer's (NYSE: PFE) Lipitor or AstraZeneca's Crestor, can lower bad LDL cholesterol by as much as 60% and increase good HDL by up to 15%.

For some patients, that's not enough, though. Taking statins alone fails to lower LDL cholesterol to healthy levels in as much as 50% of patients. Another 3%-4% of patients can't take statins because of side effects.

One option is for patients to take Merck's (NYSE: MRK) Zetia or Vytorin, which is a combination of Zetia and a statin called Zocor. Adding Zetia to a statin can lower LDL cholesterol by 25%. While it's clear that the cholesterol goes down on the laboratory test, it isn't as clear that the lower cholesterol translates into better outcomes.

A trial a few years ago failed to show that Vytorin could reduce plaque in arteries compared to a statin along. But those tests aren't perfect. The definitive answer will come from an outcomes trial, expected to read out next year.

New targetsStatins work by inhibiting HMG-CoA reductase, an enzyme in the pathway that converts a molecule called HMG-CoA into cholesterol. Zetia works by inhibiting cholesterol absorption in the intestine.

Drugmakers are working on a couple of other new targets to help lower cholesterol.

Aegerion Pharmaceutical's Juxtapid inhibits microsomal triglyceride transfer protein, which helps assemble very low-density lipoprotein, which are eventually made into LDL cholesterol in the blood stream.

Isis Pharmaceuticals (NASDAQ: ISIS) and Sanofi's Kynamro inhibits the production of apolipoprotein B, a precursor of LDL cholesterol.

Both Juxtapid and Kynamro are approved to treat a genetic disorder called homozygous familial hypercholesterolemia, which causes extremely high cholesterol levels. While both drugs are quite effective, they both have side effects that will probably keep them from being used in patients with cholesterol levels that that are marginally high.

Proprotein convertase subtilisin/kexin type 9, or PCSK9 -- the newest target drugmakers are pursuing -- looks like it's going to be a good one based on the number of different companies going after it. PCSK9 promotes the degradation of a receptor responsible for metabolizing LDL cholesterol.

Sanofi and Regeneron Pharmaceuticals (NASDAQ: REGN) are working on a drug codenamed REGN727/SAR236553 that inhibits PCSK9. In a phase 2 trial, the drug reduced LDL cholesterol by 28.9% to 67.9% compared with a 10.7% reduction in patients receiving placebo. Amgen (NASDAQ: AMGN) also has a PCSK9 inhibitor called AMG 145, which reduced LDL cholesterol by up to 66% in patients already taking a statin.

Alnylam Pharmaceuticals recently partnered with The Medicines Company to develop its PCSK9 drug. Rather than inhibiting the protein directly, Alnylam uses an RNAi strategy to lower the production of the protein.

In Pfizer's trial of RN-316, patients taking statins saw their cholesterol fall by 80% after the first treatment. Some patients saw their levels fall so low, they didn't qualify for a second injection.

Roche also has PCSK9 drugs in development. The Swiss pharma has kept its data close to its chest, reportedly because of all the competition.

Added benefitStatins aren't going anywhere given their effectiveness and tolerability. AstraZeneca has to worry more about competition from generic Lipitor than it does PCSK9 inhibitors.

But there's still a nice large market of people that could take a statin and a PCSK9 inhibitor. Investors should keep an eye on the space, but it'll be difficult to pick a winner until we see data from large phase 3 trials next year.

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